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Found 35817 matches. Displaying 11-20
Lee IH, Procko C, Lu Y, Shaham S
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Stress-Induced Neural Plasticity Mediated by Glial GPCR REMO-1 Promotes C. elegans Adaptive Behavior

CELL REPORTS 2021 JAN 12; 34(2):? Article 108607
Animal nervous systems remodel following stress. Although global stress-dependent changes are well documented, contributions of individual neuron remodeling events to animal behavior modification are challenging to study. In response to environmental insults, C. elegans become stress-resistant dauers. Dauer entry induces amphid sensory organ remodeling in which bilateral AMsh glial cells expand and fuse, allowing embedded AWC chemosensory neurons to extend sensory receptive endings. We show that amphid remodeling correlates with accelerated dauer exit upon exposure to favorable conditions and identify a G protein-coupled receptor, REMO-1, driving AMsh glia fusion, AWC neuron remodeling, and dauer exit. REMO-1 is expressed in and localizes to AMsh glia tips, is dispensable for other remodeling events, and promotes stress-induced expression of the remodeling receptor tyrosine kinase VER-1. Our results demonstrate how single-neuron structural changes affect animal behavior, identify key glial roles in stress-induced nervous system plasticity, and demonstrate that remodeling primes animals to respond to favorable conditions.
Gao DX, Ciancanelli MJ, Zhang P, Harschnitz O, Bondet V, Hasek M, Chen J, Mu X, Itan Y, Cobat A, Sancho-Shimizu V, Bigio B, Lorenzo L, Ciceri G, McAlpine J, Anguiano E, Jouanguy E, Chaussabel D, Meyts I, Diamond MS, Abel L, Hur S, Smith GA, Notarangelo L, Duffy D, Studer L, Casanova JL, Zhang SY
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TLR3 controls constitutive IFN-beta antiviral immunity in human fibroblasts and cortical neurons

JOURNAL OF CLINICAL INVESTIGATION 2021 JAN 4; 131(1):? Article e134529
Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-alpha/beta induction by the TLR3 recognition of dsRNA viral intermediates or by-products. However, we show here that human TLR3 controls constitutive levels of IFNB mRNA and secreted bioactive IFN-beta protein, and thereby also controls constitutive mRNA levels for IFN-stimulated genes (ISGs) in fibroblasts. Tlr3(-/-) mouse embryonic fibroblasts also have lower basal ISG levels. Moreover, human TLR3 controls basal levels of IFN-beta secretion and ISG mRNA in induced pluripotent stem cell-derived cortical neurons. Consistently, TLR3-deficient human fibroblasts and cortical neurons are vulnerable not only to both VSV and HSV-1, but also to several other families of viruses. The mechanism by which TLR3 restricts viral growth in human fibroblasts and cortical neurons in vitro and, by inference, by which the human CNS prevents infection by HSV-1 in vivo, is therefore based on the control of early viral infection by basal IFN-1 beta immunity.
Goncalves-Carneiro D, Bieniasz PD
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Mechanisms of Attenuation by Genetic Recoding of Viruses

MBIO 2021 JAN-FEB; 12(1):? Article e02238-20
The development of safe and effective vaccines against viruses is central to disease control. With advancements in DNA synthesis technology, the production of synthetic viral genomes has fueled many research efforts that aim to generate attenuated viruses by introducing synonymous mutations. Elucidation of the mechanisms underlying virus attenuation through synonymous mutagenesis is revealing interesting new biology that can be exploited for vaccine development. Here, we review recent advancements in this field of synthetic virology and focus on the molecular mechanisms of attenuation by genetic recoding of viruses. We highlight the action of the zinc finger antiviral protein (ZAP) and RNase L, two proteins involved in the inhibition of viruses enriched for CpG and UpA dinucleotides, that are often the products of virus recoding algorithms. Additionally, we discuss current challenges in the field as well as studies that may illuminate how other host functions, such as translation, are potentially involved in the attenuation of recoded viruses.
Ogishi M, Yang R, Gruber C, Zhang P, Pelham SJ, Spaan AN, Rosain J, Chbihi M, Han JE, Rao VK, Kainulainen L, Bustamante J, Boisson B, Bogunovic D, Boisson-Dupuis S, Casanova JL
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Multibatch Cytometry Data Integration for Optimal Immunophenotyping

JOURNAL OF IMMUNOLOGY 2021 JAN 1; 206(1):206-213
High-dimensional cytometry is a powerful technique for deciphering the immunopathological factors common to multiple individuals. However, rational comparisons of multiple batches of experiments performed on different occasions or at different sites are challenging because of batch effects. In this study, we describe the integration of multibatch cytometry datasets (iMUBAC), a flexible, scalable, and robust computational framework for unsupervised cell-type identification across multiple batches of highdimensional cytometry datasets, even without technical replicates. After overlaying cells from multiple healthy controls across batches, iMUBAC learns batch-specific cell-type classification boundaries and identifies aberrant immunophenotypes in patient samples from multiple batches in a unified manner. We illustrate unbiased and streamlined immunophenotyping using both public and in-house mass cytometry and spectral flow cytometry datasets. The method is available as the R package iMUBAC (https:// github.com/casanova-lab/iMUBAC).
Hendricks AJ, Hsiao JL, Lowes MA, Shi VY
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A Comparison of International Management Guidelines for Hidradenitis Suppurativa

DERMATOLOGY 2021 JAN; 237(1):81-96
Hidradenitis suppurativa (HS) is a chronic inflammatory dermatosis that imparts a significant burden on patients and presents a management challenge for healthcare providers. As attention to this debilitating condition has grown over recent years, our understanding of HS pathogenesis and optimal treatment approaches continues to evolve. Nine HS treatment guidelines developed by various expert organizations have been published, encompassing therapeutic modalities ranging from topical agents to systemic therapies to procedural interventions. These guidelines demonstrate significant overlap in treatment recommendations and have all been published within the last 5 years. Therefore, we aim to compare and synthesize the recommendations of international HS treatment guidelines and to encourage inter-organizational communication for the development of consensus or staggered publication of recommendations for HS management.
Wang ZJ, Lorenzi JCC, Muecksch F, Finkin S, Viant C, Gaebler C, Cipolla M, Hoffman HH, Oliveira TY, Oren DA, Ramos V, Nogueira L, Michailidis E, Robbiani DF, Gazumyan A, Rice CM, Hatziioannou T, Bieniasz PD, Caskey M, Nussenzweig MC
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Enhanced SARS-CoV-2 neutralization by dimeric IgA

SCIENCE TRANSLATIONAL MEDICINE 2021 JAN 20; 13(577):? Article eabf1555
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), primarily infects cells at mucosal surfaces. Serum neutralizing antibody responses are variable and generally low in individuals that suffer mild forms of COVID-19. Although potent immunoglobulin G (IgG) antibodies can neutralize the virus, less is known about secretory antibodies such as IgA that might affect the initial viral spread and transmissibility from the mucosa. Here, we characterize the IgA response to SARS-CoV-2 in a cohort of 149 convalescent individuals after diagnosis with COVID-19. IgA responses in plasma generally correlated with IgG responses. Furthermore, clones of IgM-, IgG-, and IgA-producing B cells were derived from common progenitor cells. Plasma IgA monomers specific to SARS-CoV-2 proteins were demonstrated to be twofold less potent than IgG equivalents. However, IgA dimers, the primary form of antibody in the nasopharynx, were, on average, 15 times more potent than IgA monomers against the same target. Thus, dimeric IgA responses may be particularly valuable for protection against SARS-CoV-2 and for vaccine efficacy.
Huh D, Passarelli MC, Gao J, Dusmatova SN, Goin C, Fish L, Pinzaru AM, Molina H, Ren ZJ, McMillan EA, Asgharian H, Goodarzi H, Tavazoie SF
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A stress-induced tyrosine-tRNA depletion response mediates codon-based translational repression and growth suppression

EMBO JOURNAL 2021 JAN 15; 40(2):? Article e106696
Eukaryotic transfer RNAs can become selectively fragmented upon various stresses, generating tRNA-derived small RNA fragments. Such fragmentation has been reported to impact a small fraction of the tRNA pool and thus presumed to not directly impact translation. We report that oxidative stress can rapidly generate tyrosine-tRNA(GUA) fragments in human cells-causing significant depletion of the precursor tRNA. Tyrosine-tRNA(GUA) depletion impaired translation of growth and metabolic genes enriched in cognate tyrosine codons. Depletion of tyrosine tRNA(GUA) or its translationally regulated targets USP3 and SCD repressed proliferation-revealing a dedicated tRNA-regulated growth-suppressive pathway for oxidative stress response. Tyrosine fragments are generated in a DIS3L2 exoribonuclease-dependent manner and inhibit hnRNPA1-mediated transcript destabilization. Moreover, tyrosine fragmentation is conserved in C. elegans. Thus, tRNA fragmentation can coordinately generate trans-acting small RNAs and functionally deplete a tRNA. Our findings reveal the existence of an underlying adaptive codon-based regulatory response inherent to the genetic code.
Slaughter MJ, Shanle EK, Khan A, Chua KF, Hong T, Boxer LD, Allis CD, Josefowicz SZ, Garcia BA, Rothbart SB, Strahl BD, Davis IJ
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HDAC inhibition results in widespread alteration of the histone acetylation landscape and BRD4 targeting to gene bodies

CELL REPORTS 2021 JAN 19; 34(3):? Article 108638
Histone acetylation levels are regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) that antagonistically control the overall balance of this post-translational modification. HDAC inhibitors (HDACi) are potent agents that disrupt this balance and are used clinically to treat diseases including cancer. Despite their use, little is known about their effects on chromatin regulators, particularly those that signal through lysine acetylation. We apply quantitative genomic and proteomic approaches to demonstrate that HDACi robustly increases a low-abundance histone 4 polyacetylation state, which serves as a preferred binding substrate for several bromodomain-containing proteins, including BRD4. Increased H4 polyacetylation occurs in transcribed genes and correlates with the targeting of BRD4. Collectively, these results suggest that HDAC inhibition functions, at least in part, through expansion of a rare histone acetylation state, which then retargets lysine-acetyl readers associated with changes in gene expression, partially mimicking the effect of bromodomain inhibition.
Divangahi M, Aaby P, Khader SA, Barreiro LB, Bekkering S, Chavakis T, van Crevel R, Curtis N, DiNardo AR, Dominguez-Andres J, Duivenwoorden R, Fanucchi S, Fayad Z, Fuchs E, Hamon M, Jeffrey KL, Khan N, Joosten LAB, Kaufmann E, Latz E, Matarese G, van der Meer JWM, Mhlanga M, Moorlag SJCFM, Mulder WJM, Naik S, Novakovic B, O'Neill L, Ochando J, Ozato K, Riksen NP, Sauerwein R, Sherwood ER, Schlitzer A, Schultze JL, Sieweke MH, Benn CS, Stunnenberg H, Sun J, van de Veerdonk FL, Weis S, Williams DL, Xavier R, Netea MG
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Trained immunity, tolerance, priming and differentiation: distinct immunological processes

NATURE IMMUNOLOGY 2021 JAN; 22(1):2-6
The similarities and differences between trained immunity and other immune processes are the subject of intense interrogation. Therefore, a consensus on the definition of trained immunity in both in vitro and in vivo settings, as well as in experimental models and human subjects, is necessary for advancing this field of research. Here we aim to establish a common framework that describes the experimental standards for defining trained immunity.
Nishimura Y, Donau OK, Dias J, Ferrando-Martinez S, Jesteadt E, Sadjadpour R, Gautam R, Buckler-White A, Geleziunas R, Koup RA, Nussenzweig MC, Martin MA
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Immunotherapy during the acute SHIV infection of macaques confers long-term suppression of viremia

JOURNAL OF EXPERIMENTAL MEDICINE 2021 JAN 4; 218(1):? Article e20201214
We report that combination bNAb immunotherapy initiated on day 3 post-infection (PI) maintained durable CD8(+) T cell-mediated suppression of SHIVAD8 viremia and preinoculation levels of CD4(+) T cells in 9 of 13 treated monkeys during nearly 6 yr of observation, as assessed by successive CD8(+) T cell-depletion experiments. In an extension of that study, two treatment interventions (bNAbs alone or cART plus bNAbs) beginning on week 2 PI were conducted and conferred controller status to 7 of 12 monkeys that was also dependent on control mediated by CD8(+) cells. However, the median time to suppression of plasma viremia following intervention on week 2 was markedly delayed (85 wk) compared with combination bNAb immunotherapy initiated on day 3 (39 wk). In both cases, the principal correlate of virus control was the induction of CD8(+) T cellular immunity.